Afraid of Hippocampal aging? Exercise!

Mild exercise increases dihydrotestosterone in hippocampus providing evidence for androgenic mediation of neurogenesis

1. Masahiro Okamoto^a, 
2. Yasushi Hojo^b, 
3. Koshiro Inoue^a, 
4. Takashi Matsui^a,
5. Suguru Kawato^b, 
6. Bruce S. McEwen^c,¹, and 
7. Hideaki Soya^a,¹

-Author Affiliations

1. ^aLaboratory of Exercise Biochemistry and Neuroendocrinology, Faculty of Health and Sports Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8574, Japan;
2. ^bDepartment of Biophysics and Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Meguro, Tokyo 153-8902, Japan; and
3. ^cLaboratory of Neuroendocrinology, The Rockefeller University, New York,NY 10006

1. Contributed by Bruce S. McEwen, June 20, 2012 (sent for review December 10, 2011)

Abstract

Mild exercise activates hippocampal neurons through the glutamatergic pathway and also promotes adult hippocampal neurogenesis (AHN). We hypothesized that such exercise could enhance local androgen synthesis and cause AHN because hippocampal steroid synthesis is facilitated by activated neurons via N-methyl-D-aspartate receptors. Here we addressed this question using a mild-intense treadmill running model that has been shown to be a potent AHN stimulator. A mass-spectrometric analysis demonstrated that hippocampal dihydrotestosterone increased significantly, whereas testosterone levels did not increase significantly after 2 wk of treadmill running in both orchidectomized (ORX) and sham castrated (Sham) male rats. Furthermore, analysis of mRNA expression for the two isoforms of 5α-reductases (srd5a1, srd5a2) and for androgen receptor (AR) revealed that both increased in the hippocampus after exercise, even in ORX rats. All rats were injected twice with 5′-bromo-2′deoxyuridine (50 mg/kg body weight, i.p.) on the day before training. Mild exercise significantly increased AHN in both ORX and Sham rats. Moreover, the increase of doublecortin or 5′-bromo-2′deoxyuridine/NeuN-positive cells in ORX rats was blocked by s.c. flutamide, an AR antagonist. It was also found that application of an estrogen receptor antagonist, tamoxifen, did not suppress exercise-induced AHN. These results support the hypothesis that, in male animals, mild exercise enhances hippocampal synthesis of dihydrotestosterone and increases AHN via androgenenic mediation.

• neurosteroid
 
• exercise-induced neurogenesis
 
• low intensity exercise
• de novo synthesis
 
• paracrine

Footnotes

• ↵¹To whom correspondence may be addressed. E-mail:mcewen@mail.rockefeller.edu or hsoya@taiiku.tsukuba.ac.jp.